Media type: E-Article Title: Small potent ligands to the insulin‐regulated aminopeptidase (IRAP)/AT4 receptor Contributor: Axén, Andreas; Andersson, Hanna; Lindeberg, Gunnar; Rönnholm, Harriet; Kortesmaa, Jarkko; Demaegdt, Heidi; Vauquelin, Georges; Karlén, Anders; Hallberg, Mathias imprint: Wiley, 2007 Published in: Journal of Peptide Science Language: English DOI: 10.1002/psc.859 ISSN: 1075-2617; 1099-1387 Keywords: Organic Chemistry ; Drug Discovery ; Pharmacology ; Molecular Biology ; Molecular Medicine ; General Medicine ; Biochemistry ; Structural Biology Origination: Footnote: Description: <jats:title>Abstract</jats:title><jats:p>Angiotensin IV analogs encompassing aromatic scaffolds replacing parts of the backbone of angiotensin IV have been synthesized and evaluated in biological assays. Several of the ligands displayed high affinities to the insulin‐regulated aminopeptidase (IRAP)/AT<jats:sub>4</jats:sub> receptor. Displacement of the <jats:italic>C</jats:italic>‐terminal of angiotensin IV with an <jats:italic>o</jats:italic>‐substituted aryl acetic acid derivative delivered the ligand <jats:bold>4</jats:bold>, which exhibited the highest binding affinity (<jats:italic>K</jats:italic><jats:sub>i</jats:sub> = 1.9 n<jats:sc>M</jats:sc>). The high affinity of this ligand provides support to the hypothesis that angiotensin IV adopts a γ‐turn in the <jats:italic>C</jats:italic>‐terminal of its bioactive conformation.</jats:p><jats:p>Ligand (<jats:bold>4)</jats:bold> inhibits both human IRAP and aminopeptidase N‐activity and induces proliferation of adult neural stem cells at low concentrations. Furthermore, ligand <jats:bold>4</jats:bold> is degraded considerably more slowly in membrane preparations than angiotensin IV. Hence, it might constitute a suitable research tool for biological studies of the (IRAP)/AT<jats:sub>4</jats:sub> receptor. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.</jats:p>